Inhibitors of leukotriene A4 hydrolase

ABSTRACT

The present invention is directed to compounds encompassed by the Formula (I): 
                         
pharmaceutical compositions thereof, methods for inhibiting LTA-4 hydrolase, and methods for the treatment of a disease and disorder which is ameliorated by the inhibition of LTA4 h  activity. Non-limiting examples of such diseases and conditions include inflammatory and autoimmune diseases and disorders.

RELATED APPLICATIONS

This application is a continuation of International Application No.PCT/US2014/027428, which designated the United States and was filed onMar. 14, 2014, published in English, which claims the benefit of U.S.Provisional Application No. 61/781,193, filed on Mar. 14, 2013. Theentire teachings of the above application are incorporated herein byreference.

BACKGROUND OF THE INVENTION

Leukotriene B₄ (LTB₄) is a potent pro-inflammatory activator ofinflammatory cells, including neutrophils (J. Palmblad, J. Rheumatol.1984, 13(2):163-172), eosinophils (A. M. Tager, et al., J. Exp. Med.2000, 192(3):439-446), monocytes (N. Dugas et al., Immunol. 1996,88(3):384-388), macrophages (L. Gagnon et al., Agents Actions 1989,34(1-2):172-174), T cells (H. Morita et al., Biochem. Biophys. Res.Commun. 1999, 264(2):321-326) and B cells (B. Dugas et al., J.Immunol.1990, 145(10):3405-3411). Immune cell priming and activation byLTB₄ can promote chemotaxis, adhesion, free radical release,degranulation and cytokine release. LTB₄ stimulates T-cell proliferationand cytokine release in response to IL-2, concanavalin-A and CD3ligation (H. Morita et al., Biochem. Biophys. Res. Commun. 1999,264(2):321-326). LTB₄ is a chemoattractant for T-cells creating afunctional link between early innate and late adaptive immune responsesto inflammation (K. Goodarzi, et al., Nat. Immunol. 2003, 4:965-973; V.L. Ott, et al., Nat. Immunol. 2003, 4:974-981; A. M. Tager, et al., Nat.Immunol. 2003, 4:982-990). There is substantial evidence that LTB₄ playsa significant role in the amplification of many inflammatory diseasestates (R. A. Lewis et al., N. Engl. J. Med. 1990, 323:645; W. R.Henderson, Ann. Intern. Med. 1994, 121:684) including asthma (D. A.Munafo et al., J. Clin. Invest. 1994, 93(3):1042-1050), inflammatorybowel disease (IBD) (P. Sharon and W. F. Stenson, Gastroenterology 1984,86(3):453-460), chronic obstructive pulmonary disease (COPD) (P. J.Barnes, Respiration 2001, 68(5):441-448), arthritis (R. J. Griffiths etal., Proc. Natl. Acad. Sci. U.S.A. 1995, 92(2):517-521; F. Tsuji et al.,Life Sci. 1998 64(3):L51-L56), psoriasis (K. Ikai, J. Dermatol. Sci.1999, 21(3):135-146; Y. I. Zhu and M. J. Stiller, Skin Pharmacol. Appl.Skin Physiol. 2000, 13(5):235-245), and atherosclerosis (E. B.Friedrich, et al., Arterioscler. Thromb. Vasc. Biol. 2003, 23:1761-1767;K. Subbarao, et al., Arterioscler. Thromb. Vasc. Biol. 2004, 24:369-375;A. Helgadottir, et al., Nat. Genet. 2004, 36:233-239; V. R. Jala, etal., Trends in Immun. 2004, 25:315-322). LTB₄ also simulates theproduction of various cytokines and may play a role in immunoregulation(A. W. Ford-Hutchinson, Immunology 1990, 10:1). Furthermore, it has beenshown that LTB₄ levels are elevated in brochoalveolar lavage fluid frompatients with scleroderma lung disease (see Kowal-Bielecka, O. et al.,Arthritis Rheum.(Nov. 30, 2005), Vol. 52, No. 12, pp. 3783-3791).Therefore, a therapeutic agent that inhibits the biosynthesis of LTB4 orthe response of cells to LTB₄ may be useful for the treatment of theseinflammatory conditions.

The biosynthesis of LTB₄ from arachidonic acid (AA) involves the actionof three enzymes: phospholipase A₂ (PLA₂), to release AA from themembrane lipids; 5-lipoxygenase (5-LO), to form the unstable epoxideLeukotriene A₄ (LTA₄); and leukotriene A₄ hydrolase (LTA₄-h), to formLTB₄ (A. W. Ford-Hutchinson, et al., Annu. Rev. Biochem. 1994,63:383-347). The cysteinyl leukotrienes are formed by the addition ofglutathione to LTA₄ by the action of LTC₄ synthase (Aharony, D., Am. J.Respir. Crit. Care Med. 1998, 157 (6, Pt 2), S214-S218) into thepro-inflammatory cysteinyl leukotrienes LTC₄, LTD₄ and LTE₄. Analternative path for LTA₄ is conversion via transcellular biosynthesisand the action of lipoxygenases into lipoxin A₄ (LXA₄) and lipoxin B₄(LXB₄) (C. N. Serhan, Prostaglandins 1997, 53:107-137).

LTA₄-h is a monomeric, soluble 69 kD zinc metalloenzyme. A highresolution crystal structure of recombinant LTA₄-h with bound inhibitorshas been obtained (M. M. Thunissen et al., Nat Struct. Biol. 2001, 8(2):131-135). LTA₄-h is a bifunctional zinc-dependent metalloenzyme of theM1 class of metallohydrolases. It catalyses two reactions: thestereospecific epoxide hydrolase reaction to convert LTA₄ to LTB₄ and apeptidase cleavage of chromogenic substrates. The Zn center is criticalto both activities. LTA₄-h is related to aminopeptidases M and B, whichhave no LTA₄-hydrolase activity. LTA₄-h has high substrate specificity,accepting only a 5,6-trans-epoxide with a free carboxylic acid at C-1 ofthe fatty acid. The double-bond geometry of the substrate is essentialfor catalysis. In contrast, LTA₄-h peptidase activity appears to bepromiscuous, cleaving nitroanilide and 2-naphthylamide derivatives ofvarious amino acids, e.g. in particular alanine and arginine.Arg-Gly-Asp, Arg-Gly-Gly, and Arg-His-Phe tripeptides are hydrolyzedwith specificity constants (k_(cat)/K_(m)) similar to the epoxidehydrolase reaction. There is no known physiological peptide substratefor LTA₄-h.

LTA₄-h is widely expressed as a soluble intracellular enzyme inintestine, spleen, lung and kidney. High activity levels are found inneutrophils, monocytes, lymphocytes and erythrocytes. Tissue macrophagescan have high LTA₄-h levels. An interesting feature is that the cellulardistribution of LTA₄-h and 5-LO are distinct, requiring close appositionof cells such as neutrophils and epithelial cells for efficienttranscellular LTB₄ synthesis. Many studies support this concept,including data from bone marrow chimeras derived from LTA₄-h^(−/−) and5-LO^(−/−) mice (J. E. Fabre et al., J. Clin. Invest. 2002,109(10):1373-1380).

Studies have shown that introduction of exogenous LTB₄ into normaltissues can induce inflammatory symptoms (R. D. R. Camp et al., Br. J.Pharmacol. 1983, 80(3):497-502; R. Camp et al., J. Invest. Dermatol.1984, 82(2):202-204). Elevated levels of LTB₄ have been observed in anumber of inflammatory diseases including inflammatory bowel disease(IBD), chronic obstructed pulmonary disease (COPD), psoriasis,rheumatoid arthritis (RA), cystic fibrosis, multiple sclerosis (MS), andasthma (S. W. Crooks and R. S. Stockley, Int. J. Biochem. Cell Biol.1998, 30(2):173-178). Therefore, reduction of LTB₄ production by aninhibitor of LTA₄-h activity would be predicted to have therapeuticpotential in a wide range of diseases. This idea is supported by a studyof LTA₄-h-deficient mice that, while otherwise healthy, exhibitedmarkedly decreased neutrophil influx in arachidonic acid-induced earinflammation and zymosan-induced peritonitis models (R. S. Byrum et al.,J. Immunol. 1999, 163(12):6810-68129). LTA₄-h inhibitors have been shownto be effective anti-inflammatory agents in preclinical studies. Forexample, oral administration of LTA₄-h inhibitor SC57461 causedinhibition of ionophore-induced LTB4 production in mouse blood ex vivo,and in rat peritoneum in vivo (J. K. Kachur et al., J. Pharm,. Exp. Thr.2002, 300(2): 583-587). Eight weeks of treatment with the same inhibitorsignificantly improved colitis symptoms in cotton top tamarins (T. D.Penning, Curr. Pharm. Des. 2001, 7(3):163-179). The spontaneous colitisthat develops in these animals is very similar to human IBD. The resultstherefore indicate that LTA₄-h inhibitors would have therapeutic utilityin this and other human inflammatory diseases.

Events that elicit the inflammatory response include the formation ofthe pro-inflammatory mediator LTB₄, which can be blocked with an LTA₄-hinhibitor, thus providing the ability to prevent and/or treatleukotriene-mediated conditions, such as inflammation. LTA₄-h inhibitorshave been described, for example, in U.S. Pat. No. 7,737,145 and U.S.Patent Application Publication No. 20100210630A1, the contents of eachof which are incorporated by reference herein.

It would be advantageous to develop additional LTA₄-h inhibitors.

SUMMARY OF THE INVENTION

The present invention is directed to compounds encompassed by theFormula (I), pharmaceutical compositions thereof, methods for inhibitingLTA₄ hydrolase, and methods for the treatment of a disease and disorderwhich is ameliorated by the inhibition of LTA₄-h activity. Non-limitingexamples of such diseases and conditions include inflammatory diseasesand disorder, autoimmune diseases and disorders and cancer.

In one embodiment, the invention is directed to a compound having theFormula (I):

wherein:

-   R is i) the group;

or

-   -   ii) the group;

or

-   -   iii) an optionally substituted heteroaryl;    -   n₁, n₂, and n₃ are each independently 0 to 2;    -   r is 0 to 4;    -   R^(1a), R^(1b), R^(1c), R^(1d) and R^(1e) are each independently        hydrogen, OR¹⁰, C(O)OR¹⁰, C(O)R¹⁰, optionally substituted C₁-C₁₂        alkyl, optionally substituted C₂-C₁₂ alkenyl, optionally        substituted C₂-C₁₂ alkynyl, optionally substituted C₃-C₁₅        cycloalkyl, optionally substituted C₃-C₁₅ cycloalkenyl, halo,        cyano, optionally substituted aryl, optionally substituted        heteroaryl, or optionally substituted heterocyclyl;

R^(1v), R^(1w), R^(1x), R^(1y) and R^(1z) are each independentlyhydrogen or fluoro;

R³ is a direct bond, —O—, —R¹²—O—, —O—R¹²—, —O—R¹²—O—, an optionallysubstituted straight or branched C₁ to C₁₂ alkylene chain, an optionallysubstituted straight or branched C₂ to C₁₂ alkenylene chain, or anoptionally substituted straight or branched C₃ to C₁₂ alkynylene chain;

R⁴ is a direct bond, —O—R^(12a), an optionally substituted straight orbranched C₁ to C₁₂ alkylene chain, an optionally substituted straight orbranched C₂ to C₁₂ alkenylene chain, or an optionally substitutedstraight or branched C₃ to C₁₂ alkynylene chain;

R⁷ is hydrogen, OR¹⁰, C(O)R¹⁰, C(O)OR¹⁰, C(O)—R¹³—N(R¹⁰)R¹¹,N(R¹⁰)C(O)N(R¹⁰)R¹¹, optionally substituted C₁-C₁₂ alkyl, optionallysubstituted C₂-C₁₂ alkenyl, optionally substituted C₂-C₁₂ alkynyl,optionally substituted C₃-C₁₅ cycloalkyl, optionally substituted C₃-C₁₅cycloalkenyl, optionally substituted aryl, optionally substitutedheteroaryl, and optionally substituted heterocyclyl;

each R⁹ is independently —OR¹⁰, optionally substituted C₁-C₁₂ alkyl,optionally substituted C₂-C₁₂ alkenyl, optionally substituted C₂-C₁₂alkynyl, halo, aryl, or heteroaryl;

each R¹⁰ and R¹¹ is independently hydrogen, optionally substitutedC₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl, optionallysubstituted C₂-C₁₂ alkynyl, optionally substituted C₃-C₁₅ cycloalkyl,optionally substituted C₃-C₁₅ cycloalkenyl, optionally substituted aryl,optionally substituted heteroaryl, and optionally substitutedheterocyclyl;

or R¹⁰ and R¹¹, together with the nitrogen to which they are attached,form an optionally substituted N-heterocyclyl or an optionallysubstituted N-heteroaryl;

R¹² is an optionally substituted straight or branched C₁ to C₁₂ alkylenechain, an optionally substituted straight or branched C₂ to C₁₂alkenylene chain, or an optionally substituted straight or branched C₃to C₁₂ alkynylene chain;

R^(12a) is an optionally substituted straight or branched C₁ to C₁₂alkylene chain, an optionally substituted straight or branched C₂ to C₁₂alkenylene chain, or an optionally substituted straight or branched C₃to C₁₂ alkynylene chain;

each R¹³ is independently a direct bond, an optionally substitutedstraight or branched C₁ to C₁₂ alkylene chain, an optionally substitutedstraight or branched C₂ to C₁₂ alkenylene chain, or an optionallysubstituted straight or branched C₃ to C₁₂ alkynylene chain; and

R¹⁶ is selected from the group consisting of hydrogen, optionallysubstituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl,optionally substituted C₂-C₁₂ alkynyl, optionally substituted C₃-C₁₅cycloalkyl, optionally substituted C₃-C₁₅ cycloalkenyl, halo, cyano,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heterocyclyl, OR¹⁰, C(O)R¹⁰, C(O)OR¹⁰,C(O)—R¹³—N(R¹⁰)R¹¹, N(R¹⁰)C(O)N(R¹⁰)R¹¹, NR₁₀R₁₁ , and N(R₁₀)C(O)R₁₀;

Each R₁₇ is independently selected from the group consisting ofhydrogen, optionally substituted C₁-C₁₂ alkyl, optionally substitutedC₂-C₁₂ alkenyl, optionally substituted C₂-C₁₂ alkynyl, optionallysubstituted C₃-C₁₅ cycloalkyl, optionally substituted C₃-C₁₅cycloalkenyl, halo, cyano, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, OR¹⁰, NO₂,S(O)_(j)R¹⁰, S(O)jNR¹⁰R¹¹, C(O)R¹⁰, C(O)OR¹⁰, C(O)—R¹³—N(R¹⁰)R¹¹,N(R¹⁰)C(O)N(R¹⁰)R¹¹, NR₁₀R₁₁, and N(R₁₀)C(O)R₁₀;

wherein w is an integer from 1 to 3; and

j is 0, 1, or 2;

as a single stereoisomer or as a mixture of stereoisomers; or apharmaceutically acceptable salt, solvate, polymorph, clathrate,ammonium ion, N-oxide or prodrug thereof.

The invention is also directed to a pharmaceutical compositioncomprising a pharmaceutically acceptable excipient and a compound ofFormula (I), as a single stereoisomer or as a mixture of stereoisomers;or a pharmaceutically acceptable salt, solvate, polymorph, clathrate,ammonium ion, N-oxide or prodrug thereof.

Also encompassed, is a method of treating a disease or disorderameliorated by the inhibition of leukotriene A₄ (LTA₄) hydrolaseactivity in a mammal, wherein the method comprises administering to amammal in need thereof a therapeutically effective amount of a compoundof Formula (I), as a single stereoisomer or as a mixture ofstereoisomers; or a pharmaceutically acceptable salt, solvate,polymorph, clathrate, ammonium ion, N-oxide or prodrug thereof. In someaspects, the disease or disorder is an inflammatory disorder orautoimmune disorder.

DETAILED DESCRIPTION OF THE INVENTION

A description of preferred embodiments of the invention follows.

As used herein, the words “a” and “an” are meant to include one or moreunless otherwise specified. For example, the term “a cell” encompassesboth a single cell and a combination of two or more cells.

As discussed above, the present invention is directed to compounds ofFormula (I), as a single stereoisomer or as a mixture of stereoisomers;or a pharmaceutically acceptable salt, solvate, polymorph, clathrate,ammonium ion, N-oxide or prodrug thereof, pharmaceutical compositions ofany of thereof, and methods comprising administering a compound of theinvention to a subject for the treatment of disorders and diseases thatcan be ameliorated by inhibition of LTA4-h.

In some embodiments, the invention is directed to a compound of Formula(I), as a single stereoisomer or as a mixture of stereoisomers; or apharmaceutically acceptable salt, solvate, polymorph, clathrate,ammonium ion, N-oxide or prodrug thereof, wherein R₁₆ is selected fromthe group consisting of cyano, OR¹⁰, C(O)R¹⁰, C(O)OR¹⁰, andC(O)—R¹³—N(R¹⁰)R¹¹. In some embodiments, R¹⁶ is cyano.

In additional embodiments, the invention is a compound of Formula (I),as a single stereoisomer or as a mixture of stereoisomers; or apharmaceutically acceptable salt, solvate, polymorph, clathrate,ammonium ion, N-oxide or prodrug thereof, wherein w is 1 and R₁₇ isselected from the group consisting of optionally substituted aryl,optionally substituted heteroaryl and C(O)R₂₀, wherein R₂₀ is optionallysubstituted aryl and optionally substituted heteroaryl.

In yet additional aspects, the compound has the Formula (Ia):

as a single stereoisomer or as a mixture of stereoisomers; or apharmaceutically acceptable salt, solvate, polymorph, clathrate,ammonium ion, N-oxide or prodrug thereof, wherein each R₁₉ isindependently selected from the group consisting of hydrogen, optionallysubstituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl,optionally substituted C₂-C₁₂ alkynyl, optionally substituted C₃-C₁₅cycloalkyl, optionally substituted C₃-C₁₅ cycloalkenyl, halo, cyano,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heterocyclyl, OR¹⁰, NO₂, S(O)_(j)R¹⁰,S(O)_(j)NR¹⁰R¹¹, C(O)R¹⁰, C(O)OR¹⁰, C(O)—R¹³—N(R¹⁰)R¹¹,N(R¹⁰)C(O)N(R¹⁰)R¹¹, NR₁₀R₁₁, and N(R₁₀)C(O)R₁₀; and wherein z is aninteger from 1 to 5. In some embodiments, R¹⁹ is independently selectedfrom the group consisting of hydrogen, hydroxyl, halo, optionallysubstituted C₁-C₄ alkyl, C(O)R¹⁰, C(O)OR¹⁰, NO_(2,)S(O)_(j)R¹⁰ andS(O)_(j)NR¹⁰R¹¹. In certain aspects, R₁₆ is cyano.

In yet additional aspects of the invention, the compound has the Formula(Ib):

as a single stereoisomer or as a mixture of stereoisomers; or apharmaceutically acceptable salt, solvate, polymorph, clathrate,ammonium ion, N-oxide or prodrug thereof, wherein each R₂₁ isindependently selected from the group consisting of hydrogen, optionallysubstituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl,optionally substituted C₂-C₁₂ alkynyl, optionally substituted C₃-C₁₅cycloalkyl, optionally substituted C₃-C₁₅cycloalkenyl, halo, cyano,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heterocyclyl, OR¹⁰, NO₂, S(O)_(j)R¹⁰,S(O)_(j)NR¹⁰R¹¹; C(O)R¹⁰, C(O)OR¹⁰, C(O)—R¹³—N(R¹⁰)R¹¹,N(R¹⁰)C(O)N(R¹⁰)R¹¹, NR₁₀R₁₁, and N(R₁₀)C(O)R₁₀; and wherein z is aninteger from 1 to 5. In some aspects, each R²¹ is independently selectedfrom the group consisting of hydrogen, hydroxyl, halo, optionallysubstituted C₁-C₄ alkyl, C(O)R¹⁰, C(O)OR¹⁰, NO_(2,)S(O)_(j)R¹⁰ andS(O)_(j)NR¹⁰R¹¹. In yet additional aspects of the invention, each R²¹ isindependently selected from the group consisting of hydrogen, hydroxyland halo.

In yet other embodiments, the compound has the Formula (I), as a singlestereoisomer or as a mixture of stereoisomers; or a pharmaceuticallyacceptable salt, solvate, polymorph, clathrate, ammonium ion, N-oxide orprodrug thereof, wherein R¹⁷ is optionally substituted heteroaryl. Insome aspects of the invention, R¹⁷ is an optionally substitutedheteroaryl containing one or more ring nitrogen atoms. In yet additionalembodiments, R¹⁷ is and optionally substituted pyridyl.

In some embodiments, the invention is a compound described herein, as asingle stereoisomer or as a mixture of stereoisomers; or apharmaceutically acceptable salt, solvate, polymorph, clathrate,ammonium ion, N-oxide or prodrug thereof, wherein R is the group:

In certain embodiments, R^(1a) is hydrogen, C(O)OR¹⁰, C(O)R¹⁰,C(O)NR¹⁰R¹¹, optionally substituted C₁-C₁₂ alkyl, optionally substitutedC₂-C₁₂ alkenyl, optionally substituted C₂-C₁₂ alkynyl, optionallysubstituted C₃-C₁₅cycloalkyl, optionally substituted C₃-C₁₅cycloalkenyl,halo, cyano, optionally substituted aryl, optionally substitutedheteroaryl, and optionally substituted heterocyclyl. In additionalaspects, R^(1a) is hydrogen, C(O)OR¹⁰, C(O)R¹⁰, C(O)NR¹⁰R¹¹, optionallysubstituted alkyl, halo, optionally substituted phenyl, furanyl,thienyl, thiazolyl, or optionally substituted oxazolyl; and whereinR^(1b), R^(1c), , R^(1d) and R^(1e) are each hydrogen. In yet additionalembodiments, R^(1a) is halo. In additional aspects, R^(1a) is oxazolylor thiazolyl.

In additional embodiments, the invention is a compound described herein,as a single stereoisomer or as a mixture of stereoisomers; or apharmaceutically acceptable salt, solvate, polymorph, clathrate,ammonium ion, N-oxide or prodrug thereof, wherein, R is the group:

In yet another aspect, the invention is a compound described herein, asa single stereoisomer or as a mixture of stereoisomers; or apharmaceutically acceptable salt, solvate, polymorph, clathrate,ammonium ion, N-oxide or prodrug thereof, wherein R is an optionallysubstituted heteroaryl. In certain aspects, R is furanyl, oxazolyl,pyrazolyl, pyridinyl, triazolyl, thiazolyl, or benzothiazolyl, each ofwhich is optionally substituted. In some embodiments, R is an optionallysubstituted heteroaryl. In yet additional embodiments, R is furanyl,oxazolyl, pyrazolyl, pyridinyl, triazolyl, thiazolyl, or benzothiazolyl,each of which is optionally substituted.

In certain aspects, the invention is a compound described herein, as asingle stereoisomer or as a mixture of stereoisomers; or apharmaceutically acceptable salt, solvate, polymorph, clathrate,ammonium ion, N-oxide or prodrug thereof, wherein R³ is O.

In some embodiments, the invention is a compound described herein, as asingle stereoisomer or as a mixture of stereoisomers; or apharmaceutically acceptable salt, solvate, polymorph, clathrate,ammonium ion, N-oxide or prodrug thereof, wherein R⁴ is a direct bond,an optionally substituted methylene or an optionally substitutedethylene. In certain embodiments, R⁴ is methylene.

In certain embodiments, the invention is a compound described herein, asa single stereoisomer or as a mixture of stereoisomers; or apharmaceutically acceptable salt, solvate, polymorph, clathrate,ammonium ion, N-oxide or prodrug thereof, wherein R⁷ is hydrogen oroptionally substituted C₁-C₆ alkyl. In additional aspects, R⁷ ishydrogen or alkyl optionally substituted with OR¹⁰, or alkyl optionallysubstituted with NR¹⁰R¹¹. In yet another embodiment, R⁷ is hydrogen ormethyl.

Non-limiting examples of compounds encompassed by the invention areshown in Table 1 below:

TABLE 1

Compound No. X Y 1 PhO NH₂ 2 PhO

3 PhO

4 PhO

5 PhO

6 PhO

7 PhO

8 PhO

9 PhO

10 PhO

11 PhO

12 PhO

13 PhO

In Table 1 above, it will be understood that “Ph” is an abbreviation forphenyl.

It is to be understood that the specific embodiments described hereincan be taken in combination with other specific embodiments delineatedherein. It will be appreciated that the description of the presentinvention herein should be construed in congruity with the laws andprincipals of chemical bonding.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation and which is attached to the rest of the molecule by asingle bond. In some embodiments, an alkyl group has from one to twelvecarbon atoms, one to eight carbon atoms, or one to six carbon atoms.Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl,1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl(t-butyl), 3-methylhexyl, 2-methylhexyl, and the like. An optionallysubstituted alkyl group can by an alkyl group substituted with one ormore substituents described in detail below. Non-limiting examples ofoptionally substituted alkyls include haloalkyl, alkyl substituted withcyano, optionally substituted aralkyl, optionally substitutedheteroarylalkyl, optionally substituted cycoalklylalkyl, optionallysubstituted heterocycloalkyl, alkyl substituted with an amino group,alkyls substituted with hydroxyl or alkoxy, and the like.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond. In some cases, an alkenyl can have from two totwelve carbon atoms, or two to eight carbon atoms. An alkenyl isattached to the rest of the molecule by a single bond, for example,ethenyl, prop-1-enyl, but-1-enyl, pent-l-enyl, penta-1,4-dienyl, and thelike. An optionally substituted alkenyl group can by an alkyl groupsubstituted with one or more substituents described in detail below.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one triple bond, optionally containing at least one double bond.In some embodiments, an alkynyl can have from two to twelve carbonatoms, or two to eight carbon atoms. An alkynyl is attached to the restof the molecule by a single bond, for example, ethynyl, propynyl,butynyl, pentynyl, hexynyl, and the like. An optionally substitutedalkynyl group can by an alkyl group substituted with one or moresubstituents described in detail below.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, for example, methylene,ethylene, propylene, n-butylene, and the like. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkylene chain to the rest of the molecule and to the radical group canbe through one carbon in the alkylene chain or through any two carbonswithin the chain. An alkylene chain can be substituted or unsubstituted.

“Alkenylene” or “alkenylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onedouble bond and having from two to twelve carbon atoms, for example,ethenylene, propenylene, n-butenylene, and the like. The alkenylenechain is attached to the rest of the molecule through a double bond or asingle bond and to the radical group through a double bond or a singlebond. The points of attachment of the alkenylene chain to the rest ofthe molecule and to the radical group can be through one carbon or anytwo carbons within the chain.

“Alkynylene” or “alkynylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onetriple bond and having from two to twelve carbon atoms, for example,propynylene, n-butynylene, and the like. The alkynylene chain isattached to the rest of the molecule through a single bond and to theradical group through a double bond or a single bond. The points ofattachment of the alkynylene chain to the rest of the molecule and tothe radical group can be through one carbon or any two carbons withinthe chain.

“Alkoxy” refers to a radical of the formula —OR_(a). where R_(a) is anoptionally substituted alkyl radical as defined above containing one totwelve carbon atoms.

“Alkoxyalkyl” refers to a radical of the formula —R_(a)—O—R_(a) whereeach R_(a) is independently an optionally substituted alkyl radical asdefined above. The oxygen atom may be bonded to any carbon in eitheralkyl radical.

“Aryl” refers to aromatic monocyclic or multicyclic hydrocarbon ringsystem consisting only of hydrogen and carbon and containing from 6 to19 carbon atoms, where the ring system may be partially or fullysaturated. Aryl groups include, but are not limited to, groups such asfluorenyl, phenyl and naphthyl.

“Aralkyl” refers to a radical of the formula —R_(a)—R_(b) where R_(a) isan optionally substituted alkyl radical and R_(b) is one or moreoptionally substituted aryl radicals, for example, benzyl,diphenylmethyl and the like. “Aralkenyl” refers to a radical of theformula —R_(c)—R_(b) where R_(c) is an optionally substituted alkenylradical and R_(b) is one or more optionally substituted aryl radicals.“Aralkynyl” refers to a radical of the formula —R_(d)—R_(b) where R_(d)is an optionally substituted alkynyl radical and R_(b) is one or moreoptionally substituted aryl radicals.

“Aryloxy” refers to a radical of the formula —OR_(b) where R_(b) is anoptionally substituted aryl group. “Aralkyloxy” refers to a radical ofthe formula —OR_(b) where R_(b) is an aralkyl group. The aralkyl part ofthe aralkyloxy radical may be optionally substituted.

“Ammonium ion” refers to a nitrogen within a compound of the inventioncontaining a positive charge due to the additional substitution of thenitrogen with an optionally substituted alkyl group as defined above.

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Hydroxy” refers to the —OH radical.

“Nitro” refers to the —NO₂ radical.

“Oxo” refers to the C(O) radical.

“Clathrates” as used herein refers to substances which fix gases,liquids or compounds as inclusion complexes so that the complex may behandled in solid form and the included constituent (or “guest” molecule)is subsequently released by the action of a solvent or by melting. Theterm “clathrate” is used interchangeably herein with the phrase“inclusion molecule” or with the phrase “inclusion complex”. Clathratesused in the instant invention are prepared from cyclodextrins.Cyclodextrins are widely known as having the ability to form clathrates(i.e., inclusion compounds) with a variety of molecules. See, forexample, Inclusion Compounds, edited by J. L. Atwood, J. E. D. Davies,and D. D. MacNicol, London, Orlando, Academic Press, 1984; Goldberg, I.,“The Significance of Molecular Type, Shape and Complementarity inClathrate Inclusion”, Topics in Current Chemistry (1988), Vol. 149, pp.2-44; Weber, E. et al., “Functional Group Assisted ClathrateFormation—Scissor-Like and Roof-Shaped Host Molecules”, Topics inCurrent Chemistry (1988), Vol. 149, pp. 45-135; and MacNicol, D. D. etal., “Clathrates and Molecular Inclusion Phenomena”, Chemical SocietyReviews (1978), Vol. 7, No. 1, pp. 65-87. Conversion into cyclodextrinclathrates is known to increase the stability and solubility of certaincompounds, thereby facilitating their use as pharmaceutical agents. See,for example, Saenger, W., “Cyclodextrin Inclusion Compounds in Researchand Industry”, Angew. Chem. Int. Ed. Engl. (1980), Vol. 19, pp. 344-362;U.S. Pat. No. 4,886,788 (Schering AG); U.S. Pat. No. 6,355,627(Takasago); U.S. Pat. No. 6,288,119 (Ono Pharmaceuticals); U.S. Pat. No.6,110,969 (Ono Pharmaceuticals); U.S. Pat. No. 6,235,780 (OnoPharmaceuticals); U.S. Pat. No. 6,262,293 (Ono Pharmaceuticals); U.S.Pat. No. 6,225,347 (Ono Pharmaceuticals); and U.S. Pat. No. 4,935,446(Ono Pharmaceuticals).

“Cyclodextrin” refers to cyclic oligosaccharides consisting of at leastsix glucopyranose units which are joined together by alpha (1-4)linkages. The oligosaccharide ring forms a torus with the primaryhydroxyl groups of the glucose residues lying on the narrow end of thetorus. The secondary glucopyranose hydroxyl groups are located on thewider end. Cyclodextrins have been shown to form inclusion complexeswith hydrophobic molecules in aqueous solutions by binding the moleculesinto their cavities. The formation of such complexes protects the“guest” molecule from loss of evaporation, from attack by oxygen,visible and ultraviolet light and from intra- and intermolecularreactions. Such complexes also serve to “fix” a volatile material untilthe complex encounters a warm moist environment, at which point thecomplex will dissolve and dissociate into the guest molecule and thecyclodextrin. For purposes of this invention, the six-glucose unitcontaining cyclodextrin is specified as α-cyclodextrin, while thecyclodextrins with seven and eight glucose residues are designated asβ-cyclodextrin and γ-cyclodextrin, respectively. The most commonalternative to the cyclodextrin nomenclature is the naming of thesecompounds as cycloamyloses.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which may include fused or bridged ring systems, having from three tofifteen carbon atoms, and which is saturated or unsaturated and attachedto the rest of the molecule by a single bond. In some aspects, acycloalkyl will have from three to ten carbon atoms. Monocyclic radicalsinclude, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example,adamantine, norbornane, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and thelike.

“Cycloalkenyl” refers to monocyclic or polycyclic hydrocarbon alkenylmoiety having 3 to fifteen carbon atoms.

The term “cycloalkynyl,” refers to a monocyclic or polycyclic alkynylmoiety having 5 to 15 more carbon atoms.

“Cycloalkylalkyl” refers to a radical of the formula —R_(a)—R_(e) whereR_(a) is an optionally substituted alkyl radical as defined above andR_(e) is an optionally substituted cycloalkyl radical as defined above.“Cycloalkylalkenyl” refers to a radical of the formula —R_(c)—R_(e)where R_(c) is an optionally substituted alkenyl radical as definedabove and R_(e) is an optionally substituted cycloalkyl radical asdefined above. “Cycloalkylalkynyl” refers to a radical of the formula—R_(d)-R_(e) where R_(d) is an optionally substituted alkynyl radical asdefined above and R_(e) is an optionally substituted cycloalkyl radicalas defined above.

“Halo” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, for example,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl,1-bromomethyl-2-bromoethyl, and the like. The alkyl part of thehaloalkyl radical may be optionally substituted.

“Haloalkenyl” refers to an alkenyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above. The alkenylpart of the haloalkyl radical may be optionally substituted.“Haloalkynyl” refers to an alkynyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above. The alkynylpart of the haloalkyl radical may be optionally substituted.

“Heterocyclyl” and “heterocyclic” refer to a stable 3- to 18-memberednon-aromatic ring radical which includes one to six heteroatoms selectedfrom the group consisting of nitrogen, oxygen and sulfur. Unless statedotherwise specifically in the specification, the heterocyclyl radicalmay be a monocyclic, bicyclic, tricyclic or tetracyclic ring system,which may include fused or bridged ring systems; and the nitrogen,carbon or sulfur atoms in the heterocyclyl radical may be optionallyoxidized; the nitrogen atom may be optionally quaternized; and theheterocyclyl radical may be partially or fully saturated. Examples ofsuch heterocyclyl radicals include, but are not limited to, azepinyl,2,5-diazabicyclo[2.2.1]heptan-2-yl, hexahydro-1H-1,4-diazepinyl,dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxiranyl, oxazolidinyl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl,tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

“N-heterocyclyl” refers to a heterocyclyl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heterocyclyl radical to the rest of the molecule is through anitrogen atom in the heterocyclyl radical. An N-heterocyclyl radical maybe optionally substituted.

“Heterocyclylalkyl,” refers to a radical of the formula —R_(a)-R_(f)where R_(a) is an optionally substituted alkyl radical as defined aboveand R_(f) is an optionally substituted heterocyclyl radical as definedabove, and if the heterocyclyl is a nitrogen-containing heterocyclyl,the heterocyclyl can be attached to the alkyl radical at the nitrogenatom or a carbon atom. “Heterocyclylalkenyl” refers to a radical of theformula —R_(e)-R_(f) where R_(c) is an optionally substituted alkenylradical as defined above and R_(f) is an optionally substitutedheterocyclyl radical as defined above, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkenyl radical at the nitrogen atom or at the carbon atom.“Heterocyclylalkynyl” refers to a radical of the formula —R_(d)-R_(f)where R_(d) is an optionally substituted alkynyl radical as definedabove and R_(f) is an optionally substituted heterocyclyl radical asdefined above, and if the heterocyclyl is a nitrogen-containingheterocyclyl, the heterocyclyl can be attached to the alkynyl radical atthe nitrogen atom or at a carbon atom.

“Heteroaryl” refers to a 3- to 18-membered fully or partially aromaticring radical which consists of one to thirteen carbon atoms and from oneto six heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur. For purposes of this invention, the heteroarylradical may be a monocyclic, bicyclic, tricyclic or tetracyclic ringsystem, which may include fused or bridged ring systems; the nitrogen,carbon or sulfur atoms in the heteroaryl radical may be optionallyoxidized; and the nitrogen atom may be optionally quaternized. Examplesinclude, but are not limited to, acridinyl, benzimidazolyl, benzindolyl,benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl,benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl,indolinyl, isoindolinyl, indolizinyl, isoxazolyl, naphthyridinyl,oxadiazolyl, 2-oxoazepinyl, oxazolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazolyl, pyridinyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, andthiophenyl (i.e. thienyl).

“N-heteroaryl” refers to an optionally substituted heteroaryl radical asdefined above containing at least one nitrogen and where the point ofattachment of the heteroaryl radical to the rest of the molecule isthrough a nitrogen atom in the heteroaryl radical.

“Heteroarylalkyl” refers to a radical of the formula —R_(a)-R_(g) whereR_(a) is an optionally substituted alkyl radical as defined above andR_(g) is an optionally substituted heteroaryl radical as defined above.“Heteroarylalkenyl” refers to a radical of the formula —R_(c)-R_(g)where R_(c) is an optionally substituted alkenyl radical as definedabove and R_(g) is an optionally substituted heteroaryl radical asdefined above. “Heteroarylalkynyl” refers to a radical of the formula—R_(d)—R_(g) where R_(d) is an optionally substituted alkynyl radical asdefined above and R_(g) is an optionally substituted heteroaryl radicalas defined above.

The term “substituted” refers to substitution by independent replacementof one, two, or three or more of the hydrogen atoms with substituentsincluding, but not limited to, —C₁-C₁₂ alkyl, —C₂-C₁₂ alkenyl, —C₂-C₁₂alkynyl, —C₃-C₁₅ cycloalkyl, —C₃-C₁₅cycloalkenyl, C₃-C₁₅ cycloalkynyl,-heterocyclic, —F, —Cl, —Br, —I, —OH, —NO₂, —N₃, —CN, —NH₂, oxo, thioxo,—NHR_(x), —NR_(x)R_(x), dialkylamino, -diarylamino, -diheteroarylamino,—OR_(x), —C(O)OR_(y), —C(O)R_(y), —C(O)C(O)R_(y), —OCO₂R_(y),—OC(O)R_(y), OC(O)C(O)R_(y), —NHC(O)R_(y), —NHCO₂R_(y),—NHC(O)C(O)R_(y), —NHC(S)NH₂, —NHC(S)NHR_(x), —NHC(NH)NH₂,—NHC(NH)NHR_(x), —NHC(NH)R_(x), —C(NH)NHR_(x), —NR_(x)C(O)R_(X),—NR_(x)CO₂R_(y), —NR_(x)C(O)C(O)R_(y), —NR_(x)C(S)NH₂,—NR_(x)C(O)NR_(x)R_(x), —NR_(x)S(O)₂NR_(x)R_(x), —NR_(x)C(S)NHR_(x),—NR_(x)C(NH)NH₂, —NR_(x)C(NH)NHR_(x), —NR_(x)C(NH)R_(x),—C(NR_(x))NHR_(x)—S(O)_(n)R_(y), —NHSO₂R_(x), —CH₂NH₂, —CH₂SO₂CH₃,—(C═NR_(x))R_(x); -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl,-heterocycloalkyl, —C₃-C₁₅-cycloalkyl, -polyalkoxyalkyl, -polyalkoxy,-methoxymethoxy, -methoxyethoxy, —SH, —S—R_(x), or -methylthiomethyl,wherein R_(x) is selected from the group consisting of hydrogen, —C₁-C₁₂alkyl, —C₂-C₁₂ alkenyl, —C₂-C₁₂ alkynyl, —C₃-C₁₅ cycloalkyl, -aryl,-heteroaryl and -heterocyclic; —R_(y) is selected from the groupconsisting of hydrogen, —C₁-C₁₂ alkyl, —C₂-C₁₂ alkenyl, —C₂-C₁₂ alkynyl,—C₃-C₁₅ cycloalkyl, -aryl, -heteroaryl, -heterocyclic, —NH₂, —NH—C₁-C ₁₂alkyl, —NH—C₂-C₁₂ alkenyl, —NH—C₂-C₁₂-alkynyl, —NH—C₃-C₁₅ cycloalkyl,—NH-aryl, —NH-heteroaryl and —NH-heterocyclic, and n is 0, 1 or 2. It isunderstood that the aryls, heteroaryls, alkyls, cycloalkyls,heterocyclics and the like can be further substituted.

“Polymorph” refers to a polymorphic form of compound of the invention.Solids exist in either amorphous or crystalline forms. In the case ofcrystalline forms, molecules are positioned in 3-dimensional latticesites. When a compound recrystallizes from a solution or slurry, it maycrystallize with different spatial lattice arrangements, a propertyreferred to as “polymorphism,” with the different crystal formsindividually being referred to as a “polymorph”. Different polymorphicforms of a given substance may differ from each other with respect toone or more physical properties, such as solubility and dissociation,true density, crystal shape, compaction behavior, flow properties,and/or solid state stability. In the case of a chemical substance thatexists in two (or more) polymorphic forms, the unstable forms generallyconvert to the more thermodynamically stable forms at a giventemperature after a sufficient period of time. When this transformationis not rapid, the thermodynamically unstable form is referred to as the“metastable” form. In general, the stable form exhibits the highestmelting point, the lowest solubility, and the maximum chemicalstability. However, the metastable form may exhibit sufficient chemicaland physical stability under normal storage conditions to permit its usein a commercial form. In this case, the metastable form, although lessstable, may exhibit properties desirable over those of the stable form,such as enhanced solubility or better oral bioavailability.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound of the invention. Thus, the term “prodrug” refers to ametabolic precursor of a compound of the invention that ispharmaceutically acceptable. A prodrug may be inactive when administeredto a subject in need thereof, but is converted in vivo to an activecompound of the invention. Prodrugs are typically rapidly transformed invivo to yield the parent compound of the invention, for example, byhydrolysis in blood. The prodrug compound often offers advantages ofsolubility, tissue compatibility or delayed release in a mammalianorganism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24(Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi,T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. SymposiumSeries, Vol. 14, and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are incorporated in full by reference herein. Theterm “prodrug” is also meant to include any covalently bonded carriers,which release the active compound of the invention in vivo when suchprodrug is administered to a mammalian subject. Prodrugs of a compoundof the invention may be prepared by modifying functional groups presentin the compound of the invention in such a way that the modificationsare cleaved, either in routine manipulation or in vivo, to the parentcompound of the invention. Prodrugs include compounds of the inventionwherein a hydroxy, amino or mercapto group is bonded to any group that,when the prodrug of the compound of the invention is administered to amammalian subject, cleaves to form a free hydroxy, free amino or freemercapto group, respectively. Examples of prodrugs include, but are notlimited to, acetate, formate and benzoate derivatives of alcohol oramine functional groups in the compounds of the invention and the like.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Mammal” includes humans and domestic animals, such as cats, dogs,swine, cattle, sheep, goats, horses, rabbits, and the like. In someembodiments, the mammal is a human.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable excipient” includes without limitation anyadjuvant, carrier, excipient, glidant, sweetening agent, diluent,preservative, dye/colorant, flavor enhancer, surfactant, wetting agent,dispersing agent, suspending agent, stabilizer, isotonic agent, solvent,or emulsifier which, for example, has been approved by the United StatesFood and Drug Administration as being acceptable for use in humans ordomestic animals.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as, but not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, deanol,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, benethamine, benzathine, ethylenediamine, glucosamine,methylglucamine, theobromine, triethanolamine, tromethamine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. Particularly preferred organic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, cholineand caffeine.

A “pharmaceutical composition” refers to a formulation of a compound ofthe invention and a medium generally accepted in the art for thedelivery of the biologically active compound to mammals, for example,humans. Such a medium includes all pharmaceutically acceptable carriers,diluents or excipients.

“Solvate” refers to an aggregate that comprises one or more molecules ofa compound of the invention with one or more molecules of solvent. Thesolvent may be water, in which case the solvate may be a hydrate.Alternatively, the solvent may be an organic solvent. Thus, thecompounds of the present invention may exist as a hydrate, including amonohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate,tetrahydrate and the like, as well as the corresponding solvated forms.The compound of the invention may be true solvates, while in othercases, the compound of the invention may merely retain adventitiouswater or be a mixture of water plus some adventitious solvent.

“Therapeutically effective amount” refers to that amount of a compoundof the invention that, when administered to a mammal, preferably ahuman, is sufficient to effect treatment, as defined below, of a diseaseor condition of interest in the mammal, preferably a human. The amountof a compound of the invention which constitutes a “therapeuticallyeffective amount” will vary depending on, for example, the activity ofthe specific compound employed; the metabolic stability and length ofaction of the compound; the age, body weight, general health, sex, anddiet of the patient; the mode and time of administration; the rate ofexcretion; the drug combination; the severity of the particular disorderor condition; and the subject undergoing therapy, but it can bedetermined routinely by one of ordinary skill in the art having regardto his own knowledge and to this disclosure.

“Treating” or “treatment” as used herein covers the treatment of thedisease or condition of interest in a mammal, preferably a human, havingthe disease or condition of interest, and includes, for example: (i)preventing the disease or condition from occurring in a mammal, inparticular, when such mammal is predisposed to the condition but has notyet been diagnosed as having it; (ii) inhibiting the disease orcondition, i.e., arresting its development; (iii) relieving the diseaseor condition, i.e., causing regression of the disease or condition; and/or (iv) stabilizing the disease or condition.

As used herein, the terms “disease” and “condition” may be usedinterchangeably or may be different in that the particular malady orcondition may not have a known causative agent (so that etiology has notyet been worked out) and it is therefore not yet recognized as a diseasebut only as an undesirable condition or syndrome, wherein a more or lessspecific set of symptoms have been identified by clinicians.

The compounds of the invention, or their pharmaceutically acceptablesalts may contain one or more asymmetric centers and may thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that maybe defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, such as for example, but notlimited to, HPLC using a chiral column. When the compounds describedherein contain olefinic double bonds or other centres of geometricasymmetry, and unless specified otherwise, it is intended that thecompounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules arenon-superimposeable mirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present invention includestautomers of any said compounds.

Compounds of the invention can be prepared using methods that have beendescribed in the literature, for example, in U.S. Pat. No. 7,737,145 andU.S. Patent Application Publication No. 20100210630A1, the contents ofeach of which are expressly incorporated by reference herein. Relevantmethods are also described, for example, in Baraldi et al. (2003), J MedChem 46:1229-1241, the contents of which are expressly incorporated byreference herein. As will be understood by the skilled artisan,diastereomers can be separated from the reaction mixture using columnchromatography.

Methods for the preparation of compounds of the invention are alsoillustrated in the Examples section below.

It will be appreciated by those skilled in the art that in the methodsdescribed herein the functional groups of intermediate compounds mayneed to be protected by suitable protecting groups. Such functionalgroups include hydroxy, amino, mercapto and carboxylic acid. Suitableprotecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl(for example, t-butyldimethylsilyl, t-butyldiphenylsilyl ortrimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitableprotecting groups for amino, amidino and guanidino includet-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protectinggroups for mercapto include —C(O)R″ (wherein R″ is alkyl, aryl orarylalkyl), p-methoxybenzyl, trityl and the like. Suitable protectinggroups for carboxylic acid include alkyl, aryl or arylalkyl esters.

Protecting groups can be added or removed in accordance with standardtechniques, which are known to one skilled in the art and as describedherein. The use of protecting groups is described in detail in Greene,T. W. and P. G. M. Wuts, Protective Groups in Organic Synthesis (1999),3rd Ed., Wiley. As one of skill in the art would appreciate, theprotecting group may also be a polymer resin such as a Wang resin, Rinkresin or a 2-chlorotrityl-chloride resin.

It will also be appreciated by those skilled in the art, although suchprotected derivatives of compounds of this invention may not possesspharmacological activity as such, they may be administered to a mammaland thereafter metabolized in the body to form compounds of theinvention which are pharmacologically active. Such derivatives maytherefore be described as “prodrugs”. All prodrugs of compounds of thisinvention are included within the scope of the invention.

It is understood that one of ordinary skill in the art would be able tomake the compounds of the invention by methods similar to the methodsdescribed herein or by methods known to one of ordinary skill in theart. In general, compounds employed as initial starting materials in thesynthesis of the compounds of the invention are well known andcommercially available. To the extent that the compounds employed asinitial starting materials are not commercially available, the compoundsmay be readily synthesized using specific references provided, or bystandard procedures commonly employed by those of ordinary skill in theart and/or found in general references text (see, for example,Comprehensive Organic Transformations, VCH Publishers Inc., 1989;Compendium of Organic Synthetic Methods, Volumes 1-10, 1974-2002, WileyInterscience; Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, 5th edition, Wiley Interscience, 2001; Advanced OrganicChemistry, 4th Edition, Part B, Reactions and Synthesis, KluwerAcademic/Plenum Publishers, 2000, etc., and references cited therein).

The following common abbreviations are used:

-   DMF for N,N-dimethylformamide-   THF for tetrahydrofuran-   TFA for trifluoroacetic acid-   EtOAc for ethyl acetate-   TMS for trimethylsilyl-   TLC for thin layer chromatography-   MeOH for methanol-   NaOH for sodium hydroxide-   Boc for t-butoxycarbonyl.

The compounds of the invention can be tested for their ability toinhibit LTA₄-h by various known assays and by assays described herein.For example, the compounds can be tested for their ability to inhibitLTA₄-h activity by assaying the compounds in the hydrolase-homogeneoustime resolved fluoroescence assay. This assay, which is a two-stepassay, measures the hydrolysis of LTA₄-h to LTB₄ by analyzing the amountof LTB₄ produced. The first step involves the enzymatic conversion ofLTA₄-h to LTB₄ and the second step involves the quantification of theLTA₄-h formed with a homogeneous time resolved fluoroescence assay.

Since LTA₄-h hydrolase is grouped with the Ml family of zincmetalloproteases (see, Rudberg, P. C. et al., J. Biol. Chem. 2002, Vol.277, page 1398-1404), the compounds of the invention can be tested inthe standard hydrolase and peptidase assay to determine the compounds'kinetic constants for binding to LTA₄-h hydrolase and for inhibitingLTB₄ synthesis (see Askonas, L. J., et al., The Journal of Pharmacologyand Experimental Therapeutics 2002, 300(2): 577-582; Penning, T. D., J.Med. Chem. 2000, 43(4): 721-735; Kull, F. et al., The Journal ofBiological Chemistry 1999, 274 (49): 34683-34690, the contents of whichare expressly incorporated by reference herein).

Compounds of the invention can also be tested for their ability asinhibitors of LTA₄-h hydrolase in the whole blood assay using human,mouse, rat or dog whole blood (see Penning, T. D. et al., J. Med. Chem.(2000), 43(4): 721-735 for a description of a human whole blood assayand a mouse whole blood assay, the contents of which are expresslyincorporated herein).

A hallmark of inflammation is the adhesion and transmigration acrossendothelium of neutrophils, eosinophils and other inflammatory cells. Asimilar process is observed for the migration of cells across polarizedepithelial cells that occur in the lung, gastrointestinal tract andother organs. Cell culture models of these processes are available andcan be used to show the ability of the compounds of the invention toinhibit the transmigration of human neutrophils across human endothelialcells and epithelial cells, including the human intestinal epithelialcell line T₈₄. Accordingly, one of ordinary skill in the art can testthe compounds of the invention for their ability to inhibit thetransmigration of human neutrophils and eosinophils across humanendothelial cells and epithelial cells by performing assays similar tothose described in Colgan, S. P., et al., J. Clin. Invest 1993, Vol. 92,No. 1, pp. 75-82, and Serhan, C. N., et al., Biochemistry 1995, Vol. 34,No. 44, pp. 14609-14615.

The air pouch model and/or the mouse zymosan-induced peritonitis modelcan be used to evaluate the in vivo efficacy of the compounds of theinvention in treating an inflammatory response. These are acuteexperimental models of inflammation characterized by infiltration ofinflammatory cells into a localized area. See, for example, the in vivoassays described in Ajuebor, M. N., et al., Immunology 1998, Vol. 95,pp. 625-630; Gronert, K., et al., Am. J. Pathol. 2001, Vol. 158, pp.3-9; Pouliot, M., et al., Biochemistry 2000, Vol. 39. pp. 4761-4768;Clish, C. B., et al., Proc. Natl. Acad. Sci. U.S.A. 1999, Vol. 96, pp.8247-8252; Hachicha, M., et al., J. Exp. Med. 1999, Vol. 189, pp.1923-30.

Animal models (i.e., in vivo assays) can also be utilized to determinethe efficacy of the compounds of the invention in treating asthma andrelated disorders of the pulmonary and respiratory tract, including, butnot limited to, asthma. See, for example, the assays described in DeSanctis, G. T. et al., Journal of Clinical Investigation 1999, Vol. 103,pp. 507-515, and Campbell, E. M., et al., J. Immunol. 1998, Vol. 161,No. 12, pp. 7047-7053.

Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration of agents for serving similar utilities. Thepharmaceutical compositions of the invention can be prepared bycombining a compound of the invention with an appropriatepharmaceutically acceptable carrier, diluent or excipient, and may beformulated into preparations in solid, semi-solid, liquid or gaseousforms, such as tablets, capsules, powders, granules, ointments,solutions, suppositories, injections, inhalants, gels, microspheres, andaerosols. Typical routes of administering such pharmaceuticalcompositions include, without limitation, oral, topical, transdermal,inhalation, parenteral, sublingual, rectal, vaginal, and intranasal. Theterm parenteral as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection or infusiontechniques. Pharmaceutical compositions of the invention are formulatedso as to allow the active ingredients contained therein to bebioavailable upon administration of the composition to a patient.Compositions that will be administered to a subject or patient take theform of one or more dosage units, where for example, a tablet may be asingle dosage unit, and a container of a compound of the invention inaerosol form may hold a plurality of dosage units. Actual methods ofpreparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see The Science and Practice ofPharmacy, 20.sup.third Edition (Philadelphia College of Pharmacy andScience, 2000). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease or condition of interest in accordance with the teachingsof this invention.

A pharmaceutical composition of the invention can be in the form of asolid or liquid. In one aspect, the carrier(s) are particulate, so thatthe compositions are, for example, in tablet or powder form. Thecarrier(s) may be liquid, with the compositions being, for example, anoral syrup, injectable liquid or an aerosol, which is useful in, forexample, inhalatory administration. When intended for oraladministration, the pharmaceutical composition can be in either solid orliquid form, where semi-solid, semi-liquid, suspension and gel forms areincluded within the forms considered herein as either solid or liquid.

As a solid composition for oral administration, the pharmaceuticalcomposition may be formulated into a powder, granule, compressed tablet,pill, capsule, chewing gum, wafer or the like form. Such a solidcomposition will typically contain one or more inert diluents or ediblecarriers. In addition, one or more of the following may be present:binders such as carboxymethylcellulose, ethyl cellulose,microcrystalline cellulose, gum tragacanth or gelatin; excipients suchas starch, lactose or dextrins, disintegrating agents such as alginicacid, sodium alginate, Primogel, corn starch and the like; lubricantssuch as magnesium stearate or Sterotex; glidants such as colloidalsilicon dioxide; sweetening agents such as sucrose or saccharin; aflavoring agent such as peppermint, methyl salicylate or orangeflavoring; and a coloring agent.

When the pharmaceutical composition is in the form of a capsule, forexample a gelatin capsule, it may contain, in addition to materials ofthe above type, a liquid carrier such as polyethylene glycol or oil.

The pharmaceutical composition can be in the form of a liquid, forexample, an elixir, syrup, solution, emulsion or suspension. The liquidcan be for oral administration or for delivery by injection, as twoexamples. When intended for oral administration, a composition cancontain, in addition to the present compounds, one or more of asweetening agent, preservatives, dye/colorant and flavor enhancer. In acomposition intended to be administered by injection, one or more of asurfactant, preservative, wetting agent, dispersing agent, suspendingagent, buffer, stabilizer and isotonic agent may be included.

The liquid pharmaceutical compositions of the invention, whethersolutions, suspensions or other like form, can include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, preferably physiological saline, Ringer's solution,isotonic sodium chloride, fixed oils such as synthetic mono ordiglycerides which may serve as the solvent or suspending medium,polyethylene glycols, glycerin, propylene glycol or other solvents;antibacterial agents such as benzyl alcohol or methyl paraben;antioxidants such as ascorbic acid or sodium bisulfite; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. The parenteral preparation can be enclosedin ampoules, disposable syringes or multiple dose vials made of glass orplastic. Physiological saline is a preferred adjuvant. An injectablepharmaceutical composition is preferably sterile.

A liquid pharmaceutical composition of the invention intended for eitherparenteral or oral administration should contain an amount of a compoundof the invention such that a suitable dosage will be obtained.Typically, this amount is at least 0.01% of a compound of the inventionin the composition. When intended for oral administration, this amountmay be varied to be between 0.1 and about 70% of the weight of thecomposition. Preferred oral pharmaceutical compositions contain betweenabout 4% and about 50% of the compound of the invention. Preferredpharmaceutical compositions and preparations according to the presentinvention are prepared so that a parenteral dosage unit contains between0.01 to 10% by weight of the compound prior to dilution of theinvention.

The pharmaceutical composition of the invention can be intended fortopical administration, in which case the carrier may suitably comprisea solution, emulsion, ointment or gel base. The base, for example, maycomprise one or more of the following: petrolatum, lanolin, polyethyleneglycols, bee wax, mineral oil, diluents such as water and alcohol, andemulsifiers and stabilizers. Thickening agents may be present in apharmaceutical composition for topical administration. If intended fortransdermal administration, the composition may include a transdermalpatch or iontophoresis device. Topical formulations may contain aconcentration of the compound of the invention from about 0.1 to about10% w/v (weight per unit volume).

The pharmaceutical composition of the invention can be intended forrectal administration, in the form, for example, of a suppository, whichwill melt in the rectum and release the drug. The composition for rectaladministration may contain an oleaginous base as a suitablenonirritating excipient. Such bases include, without limitation,lanolin, cocoa butter and polyethylene glycol.

The pharmaceutical composition of the invention can include variousmaterials, which modify the physical form of a solid or liquid dosageunit. For example, the composition can include materials that form acoating shell around the active ingredients. The materials that form thecoating shell are typically inert, and may be selected from, forexample, sugar, shellac, and other enteric coating agents.Alternatively, the active ingredients can be encased in a gelatincapsule.

The pharmaceutical composition of the invention in solid or liquid formcan include an agent that binds to the compound of the invention andthereby assists in the delivery of the compound. Suitable agents thatmay act in this capacity include a monoclonal or polyclonal antibody, aprotein or a liposome.

The pharmaceutical composition of the invention can consist of dosageunits that can be administered as an aerosol. The term aerosol is usedto denote a variety of systems ranging from those of colloidal nature tosystems consisting of pressurized packages. Delivery can be by aliquefied or compressed gas or by a suitable pump system that dispensesthe active ingredients. Aerosols of compounds of the invention may bedelivered in single phase, bi-phasic, or tri-phasic systems in order todeliver the active ingredient(s). Delivery of the aerosol includes thenecessary container, activators, valves, subcontainers, and the like,which together may form a kit. One skilled in the art, without undueexperimentation may determine preferred aerosols.

The pharmaceutical compositions of the invention cam be prepared bymethodology well known in the pharmaceutical art. For example, apharmaceutical composition intended to be administered by injection canbe prepared by combining a compound of the invention with sterile,distilled water so as to form a solution. A surfactant may be added tofacilitate the formation of a homogeneous solution or suspension.Surfactants are compounds that non-covalently interact with the compoundof the invention so as to facilitate dissolution or homogeneoussuspension of the compound in the aqueous delivery system.

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount, whichwill vary depending upon a variety of factors and can be determinedroutinely by one of ordinary skill in the art. Generally, atherapeutically effective daily dose is (for a 70 kg mammal) from about0.001 mg/kg (i.e., 0.7 mg) to about 100 mg/kg (i.e., 7.0 gm); preferablya therapeutically effective dose is (for a 70 kg mammal) from about 0.01mg/kg (i.e., 7 mg) to about 50 mg/kg (i.e., 3.5 gm); more preferably atherapeutically effective dose is (for a 70 kg mammal) from about 1mg/kg (i.e., 70 mg) to about 25 mg/kg (i.e., 1.75 gm).

Compounds of the invention, or pharmaceutically acceptable derivativesthereof, may also be administered simultaneously with, prior to, orafter administration of one or more other therapeutic agents. Suchcombination therapy includes administration of a single pharmaceuticaldosage formulation which contains a compound of the invention and one ormore additional active agents, as well as administration of the compoundof the invention and each active agent in its own separatepharmaceutical dosage formulation. For example, a compound of theinvention and the other active agent can be administered to the patienttogether in a single oral dosage composition such as a tablet orcapsule, or each agent can be administered in separate oral dosageformulations. Where separate dosage formulations are used, the compoundsof the invention and one or more additional active agents can beadministered at essentially the same time, i.e., concurrently, or atseparately staggered times, i.e., sequentially; combination therapy isunderstood to include all these regimens.

The compounds of the invention are inhibitors of LTA₄ hydrolase activityand are therefore useful in treating diseases and disorders which areameliorated by the inhibition of LTA4 hydrolase activity. Such diseasesand conditions include inflammatory and autoimmune disorders andpulmonary and respiratory tract inflammation.

Accordingly, the compounds are useful in the treatment of the followingdiseases or disorders in mammals, particularly humans: acute or chronicinflammation, anaphylactic reactions, allergic reactions, allergiccontact dermatitis, allergic rhinitis, chemical and non-specificirritant contact dermatitis, urticaria, atopic dermatitis, psoriasis,fistulas associated with Crohn's disease, pouchitis, septic or endotoxicshock, hemorrhagic shock, shock-like syndromes, capillary leak syndromesinduced by immunotherapy of cancer, acute respiratory distress syndrome,cystic fibrosis, traumatic shock, immune- and pathogen-inducedpneumonias, immune complex-mediated pulmonary injury and chronicobstructive pulmonary disease, inflammatory bowel diseases (includingulcerative colitis, Crohn's disease and post-surgical trauma),gastrointestinal ulcers, diseases associated with ischemia-reperfusioninjury (including acute myocardial ischemia and infarction, acute renalfailure, ischemic bowel disease and acute hemorrhagic or ischemicstroke), immune-complex-mediated glomerulonephritis, autoimmune diseases(including insulin-dependent diabetes mellitus, multiple sclerosis,rheumatoid arthritis, osteoarthritis and systemic lupus erythematosus),acute and chronic organ transplant rejection, transplantarteriosclerosis and fibrosis, cardiovascular disorders (includinghypertension, atherosclerosis, aneurysm, critical leg ischemia,peripheral arterial occlusive disease and Reynaud's syndrome),complications of diabetes (including diabetic nephropathy, neuropathyand retinopathy), ocular disorders (including macular degeneration andglaucoma), neurodegenerative disorders (including delayedneurodegeneration in stroke, Alzheimer's disease, Parkinson's disease,encephalitis and HIV dementia), inflammatory and neuropathic painincluding arthritic pain, periodontal disease including gingivitis, earinfections, migraine, benign prostatic hyperplasia, and cancers(including, but not limited to, leukemias and lymphomas, prostatecancer, breast cancer, lung cancer, malignant melanoma, renal carcinoma,head and neck tumors and colorectal cancer).

The compounds are also useful in treating folliculitis induced byinhibitors of epidermal growth factor (EGF) or epidermal growth factorreceptor (EGFR) kinase used in the treatment of solid tumors. Clinicaltrials have revealed folliculitis (inflammation of the hair folliclemanifested by severe acne-like skin rash on the face, chest and upperback) as a major dose-limiting side effect of such treatments. Suchfolliculitis is associated with an infiltration of neutrophilssuggesting products secreted by activated neutrophils to be the cause ofthe inflammation. The compounds of the invention inhibit neutrophil oreosinophil-mediated inflammation, and are therefore useful in treatingsuch folliculitis, thereby improving the quality of life of the treatedcancer patients but also allowing for the increase of the dosage of theEGF inhibitor or EGFR kinase inhibitor or the extension of the durationof the treatment, resulting in improved efficacy of the desiredinhibitor.

The compounds are also useful in the treatment of pulmonary andrespiratory inflammation disorders in mammals, particularly humans,including, but not limited to, asthma, chronic bronchitis,bronchiolitis, bronchiolitis obliterans (including such with organizingpneumonia), allergic inflammation of the respiratory tract (includingrhinitis and sinusitis), eosinophilic granuloma, pneumonias, pulmonaryfibroses, pulmonary manifestations of connective tissue diseases, acuteor chronic lung injury, chronic obstructive pulmonary diseases, adultrespiratory distress syndrome, and other non-infectious inflammatorydisorders of the lung characterized by eosinophil infiltration.

For example, the compounds of the invention are useful in the inhibitionof: eosinophil-mediated inflammation of the lung or tissues;neutrophil-mediated inflammation of the lung; lymphocyte-mediatedinflammation of the lung; airway hyper-responsiveness; and airway andvascular inflammation.

The compounds are also useful in the treatment of myocardial infarctionor susceptibility to myocardial infarction in mammals, particularlyhumans, transient ischemic attack, transient monocular blindness, strokeor susceptibility of stroke, claudication, peripheral arterial occlusivedisease or susceptibility to peripheral arterial occlusive disease, andacute coronary syndrome (such as unstable angina, non-ST-elevationmyocardial infarction or ST-elevation myocardial infarction). Thecompounds are also useful in the methods for reducing the risk ofmyocardial infarction, stroke or peripheral arterial occlusive diseasein mammals and reducing the risk of a second myocardial infarction orstroke.

The compounds are also useful in the treatment of atherosclerosis inmammals, particularly humans who require treatment (such as angioplasty,stents, coronary artery bypass graft) in order to restore blood flow inthe arteries (such as in the coronary arteries).

The compounds described herein can also be used in the treatment ofneurodegenerative diseases. Non-limiting examples of neurodegenerativediseases that can be treated according to a method of the invention areamyotrophic lateral sclerosis (ALS), Parkinson's disease andHuntington's disease.

The compounds of the invention can be used in the treatment of cancer.In some embodiments, the cancer is a leukemia. Specific exemplaryleukemias that can be treated by administering a compound of theinvention are Chronic Granulocytic Leukemias, Chronic B-Cell

Leukemias and Chronic Myelogenous Leukemias. The invention alsoencompasses a method of treating a solid tumor in a subject in needthereof. Non-limiting examples of solid tumors that can be treatedaccording to the methods described herein are ovarian, esophageal andhepatocellular tumors.

In certain embodiments, the invention is a method of treatingrespiratory inflammation in a subject in need thereof comprisingadministering to said subject a compound of described herein. In oneembodiment, the respiratory inflammation is cystic fibrosis.

In yet additional aspects, the invention encompasses a method oftreating an inflammatory skin condition. Non-limiting examples ofinflammatory skin conditions are atopic dermatitis, acne, psoriasis andeczema.

In some embodiments, the invention is directed to a method of treating acondition selected from the group consisting of cystic fibrosis,idiopathic pulmonary fibrosis, interstitial lung disease associated withsystemic sclerosis, atherosclerosis, osteoarthritis, Alzheimer'sdisease, osteoporosis, and type II diabetes, allergic rhinitis, acne,and gingivitis. Also encompasses is a method of treating an eosinophilicdisorder. Exemplary eosinophilic disorders are eosinophilic esophagitis,eosinophilic gastroenteritis, eosinophilic colitis, eosinophilicfasciitis, eosinophilic pneumonia, eosinophilic cystitis,hypereosinophilic syndrome and Churg Strauss Syndrome. In someembodiments, the eosinophilic disorder is eosinophilic esophagitis.

The compounds are also useful in inhibiting the synthesis of leukotrieneB₄ in both in vitro and in vivo assays.

The invention is illustrated by the following non-limiting examples.

EXEMPLIFICATION EXAMPLE 1 Preparation of Substituted Anilines

A. A solution of 4-(2-oxazolyl)phenol (10.8 g, 11.2 mmol) in DMSO (9 mL)was stirred as potassium tert-butoxide (1.5 g, 13.4 mmol) and4-fluoro-nitrobenzene (1.3 mL, 12.3 mmol) were added sequentially. Thereaction was stirred for 17 h at ambient temperature. The reaction waspoured into a cold aqueous sodium hydroxide solution (1 N). The solidwas isolated by filtration to give 2.6 g of2-[4-(4-nitrophenoxy)phenyl]oxazole.

B. A slurry of 2-[4-(4-nitrophenoxy)phenyl]oxazole (2.6 g, 9.2 mmol) ina mixture of ethyl acetate (20 mL) and methanol (100 mL) was placedunder a nitrogen atmosphere before the addition of catalyst palladium(10% on C, 0.65 g). The reaction mixture was placed under a hydrogenatmosphere at atmospheric pressure. After 3 h, the reaction mixture wasfiltered through a pad of Celite and washed with methanol. The filtratewas concentrated to give the 2.4 g of4-[4-(2-oxazolyl)phenoxy]benzenamine.

The substituted anilines described below were purchased fromSigma-Aldrich or prepared as described above.

EXAMPLE 2 Preparation of 4-(2,2,3,3,3-pentafluoropropoxy)phenylamine

A slurry of sodium hydride (1 g, 24 mmol) in DMF (75 mL) was stirred as2,2,3,3,3-pentafluoropropanol (2 mL, 20 mmol) was added over 50 min. Thereaction mixture was treated with 4-fluoro-l-nitrobenzene (2.1 mL, 20mmol) and stirred for 16 h. The reaction was quenched with water andextracted with ether. Purification using flash chromatography using agradient of ethyl acetate in hexane gave 3.7 g of1-nitro-4-(2,2,3,3,3-pentafluoropropoxy)benzene: ¹H NMR (CDCl₃, 400MHz)δ 8.21 (d, 2H), 6.94 (d, 2H), 4.43 (t, 2H).

A solution of 1-nitro-4-(2,2,3,3,3-pentafluoropropoxy)benzene (3.7 g,13.7 mmol) in methanol (50 mL) was deoxygenated by bubbling nitrogenthrough the solution before the addition of 10% Pd/C (0.37 g). Thereaction mixture was stirred and placed under a hydrogen atmosphere for16 h. The reaction was filtered through a pad of Celite and washed withmethanol. The filtrates were concentrated to give 3.4 g. Purificationusing flash chromatography using a gradient of methylene chloride inhexane gave 2.5 g of 4-(2,2,3,3,3-pentafluoropropoxy)phenylamine: ¹H NMR(CDCl₃, 400MHz) δ 6.71 (d, 2H), 6.64 (d, 2H), 4.33 (t, 2H), 3.48 (s,2H).

EXAMPLE 3 Preparation of Compound 9

A solution of 2-[Bis-(methylsulfanyl)methylene]malononitrile in absoluteethanol was treated with 4-phenoxyaniline and the mixture was heated atreflux until all starting material was consumed. Solvent was removedunder reduced pressure to yield the desired2-[(4-phenoxyphenylamino)-2-methylsulfanylmethylene]malononitrile.

A solution of desired2-[(4-phenoxyphenylamino)-2-methylsulfanylmethylene]malononitrile inabsolute ethanol was treated with hydrazine and the reaction was heatedat reflux until the starting material was consumed. The reaction wasallowed to cool and solvent removed under reduced pressure to give thedesired 1H-3-amino-4-cyano-5-(4-phenoxyphenylamino)pyrazole.

A mixture of 1H-3-amino-4-cyano-5-(4-phenoxyphenylamino)pyrazole and2-(2-nitro-3-hydroxycarboxyphenyl)-malondialdehyde were combined in aalcohol solvent and heated unitl starting material had been consumed.Solvent was removed and desired2-(4-phenoxyphenylamino)-3-cyano-6-(2-nitro-3-hydroxycarboxyphenyl)pyrazolo[1,5-a]pyrimidinewas isolated.

EXAMPLE 4 Biological Activity

Table 2 below shows the IC₅₀ values for peptidase, hydrolase and wholeblood assay (WBA) activity for exemplary compounds encompassed by theinvention. The whole blood and aminopeptidase assays were performed asdescribed in Penning et al., J. Med. Chem. 2000, 43, 721-735, andRudberg et al., J. Biol. Chem. Vol. 279, No. 26, Issue of June 25, pp.27376-27382, 2004, the contents of each of which are expresslyincorporated by reference herein. The hydrolase assay was performed asdescribed in U.S. Pat. No. 7,737,145, the contents of which areexpressly incorporated herein.

TABLE 2

IC₅₀ IC₅₀ Hydrolase Compound Peptidase (nM or % IC₅₀ WBA No. X = Y =(nM) inhibition) (nM) 1 PhO NH₂ 280 (N3) 1500 (N3) >8800 (N2) 2 PhO

260 (N2) 3700 >7200 (N2) 3 PhO

430 (N3) 39% inhibition at 3 uM >10000 (N2) 4 PhO

1700 (N2) 48% inhibition at 3 uM (N2) 5 PhO

90 (N2) 20 (N2) 1400 (N3)  490 (N2) 4900 (N2) 3000 (N2) 6 PhO

960 (N2) 15% @ 3 uM (N2) 7 PhO

30 (N3) 10 (n2) 1600 (N2) 2900 4600 (N2) 3000 (N2) 8 OPh

0% inhibition at 3 uM 9 —OPh

3.3 20% inhibition at 1 uM 10 —OPh

120 (n = 2) 20% inhibition at 1 uM 11 —OPh

270 (n = 2) 12 —OPh

84 (n = 2) 13 —OPh

13% inhibition at 1 uM

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

What is claimed is:
 1. A compound having the Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R is the group:

r is 0 to 4; R^(1a), R^(1b), R^(1c), R^(1d) and R^(1e) are eachindependently hydrogen, OR¹⁰, C(O)OR¹⁰, C(O)R¹⁰, optionally substitutedC₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl, optionallysubstituted C₂-C₁₂ alkynyl, optionally substituted C₃-C₁₅ cycloalkyl,optionally substituted C₃-C₁₅ cycloalkenyl, halo, cyano, optionallysubstituted aryl, optionally substituted heteroaryl, or optionallysubstituted heterocyclyl; R³ is —O—; R⁴ is a direct bond, —O—R^(12a), anoptionally substituted straight or branched C₁ to C₁₂ alkylene chain, anoptionally substituted straight or branched C₂ to C₁₂ alkenylene chain,or an optionally substituted straight or branched C₃ to C₁₂ alkynylenechain; R⁷ is selected from the group consisting of hydrogen, OR¹⁰,C(O)R¹⁰, C(O)OR¹⁰, C(O)—R¹³—N(R¹⁰)R¹¹, N(R¹⁰)C(O)N(R¹⁰)R¹¹, optionallysubstituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl,optionally substituted C₂-C₁₂ alkynyl, optionally substituted C₃-C₁₅cycloalkyl, optionally substituted C₃-C₁₅ cycloalkenyl, optionallysubstituted aryl, optionally substituted heteroaryl, and optionallysubstituted heterocyclyl; each R⁹ is independently —OR¹⁰, optionallysubstituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl,optionally substituted C₂-C₁₂ alkynyl, halo, aryl, or heteroaryl; eachR¹⁰ and R¹¹ is independently selected from the group consisting ofhydrogen, optionally substituted C₁-C₁₂ alkyl, optionally substitutedC₂-C₁₂ alkenyl, optionally substituted C₂-C₁₂ alkynyl, optionallysubstituted C₃-C₁₅ cycloalkyl, optionally substituted C₃-C₁₅cycloalkenyl, optionally substituted aryl, optionally substitutedheteroaryl, and optionally substituted heterocyclyl; or R¹⁰ and R¹¹,together with the nitrogen to which they are attached, form anoptionally substituted N-heterocyclyl or an optionally substitutedN-heteroaryl; R^(12a) is an optionally substituted straight or branchedC₁ to C₁₂ alkylene chain, an optionally substituted straight or branchedC₂ to C₁₂ alkenylene chain, or an optionally substituted straight orbranched C₃ to C₁₂ alkynylcnc chain; each R¹³ is independently a directbond, an optionally substituted straight or branched C₁ to C₁₂ alkylenechain, an optionally substituted straight or branched C₂ to C₁₂alkenylene chain, or an optionally substituted straight or branched C₃to C₁₂ alkynylene chain; and R¹⁶ is selected from the group consistingof hydrogen, optionally substituted C₁-C₁₂ alkyl, optionally substitutedC₂-C₁₂ alkenyl, optionally substituted C₂-C₁₂ alkynyl, optionallysubstituted C₃-C₁₅ cycloalkyl, optionally substituted C₃-C₁₅cycloalkenyl, halo, cyano, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, OR¹⁰,C(O)R¹⁰, C(O)OR¹⁰, C(O)—R¹³—N(R¹⁰)R¹¹,N(R¹⁰)C(O)N(R¹⁰)R¹¹, NR¹⁰R¹¹, andN(R¹⁰)C(O)R¹⁰; each R¹⁷ is independently selected from the groupconsisting of hydrogen, optionally substituted C₁-C₁₂ alkyl, optionallysubstituted C₂-C₁₂ alkenyl, optionally substituted C₂-C₁₂ alkynyl,optionally substituted C₃-C₁₅ cycloalkyl, optionally substituted C₃-C₁₅cycloalkenyl, halo, cyano, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, OR¹⁰, NO₂,S(O)_(j)R¹⁰, S(O)_(j)NR¹⁰R¹¹, C(O)R¹⁰, C(O)OR¹⁰, C(O)—R¹³—N(R¹⁰)R¹¹,N(R¹⁰)C(O)N(R¹⁰)R¹¹, NR¹⁰R¹¹, and N(R¹⁰)C(O)R¹⁰; wherein w is an integerfrom 1 to 3; and j is 0, 1, or
 2. 2. The compound of claim 1, whereinR¹⁶ is cyano; or a pharmaceutically acceptable salt thereof.
 3. Thecompound of claim 1, wherein w is 1 and R¹⁷ is selected from the groupconsisting of optionally substituted aryl, optionally substitutedheteroaryl, and C(O)R₂₀, wherein R₂₀ is selected from the groupconsisting of optionally substituted aryl and optionally substitutedheteroaryl; or a pharmaceutically acceptable salt thereof.
 4. Thecompound of claim 1, wherein the compound has the Formula (Ia):

or a pharmaceutically acceptable salt thereof; wherein each R¹⁹ isindependently selected from the group consisting of hydrogen, optionallysubstituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl,optionally substituted C₂-C₁₂ alkynyl, optionally substituted C₃-C₁₅cycloalkyl, optionally substituted C₃-C₁₅ cycloalkenyl, halo, cyano,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heterocyclyl, OR¹⁰, NO₂, S(O)_(j)R¹⁰,S(O)_(j)NR¹⁰R¹¹; C(O)R¹⁰, C(O)OR¹⁰, C(O)—R¹³—N(R¹⁰)R¹¹,N(R¹⁰)C(O)N(R¹⁰)R¹¹, NR¹⁰R¹¹, and N(R¹⁰)C(O)R¹⁰; wherein z is an integerfrom 1 to
 5. 5. The compound of claim 4, wherein z is 1 or 2, and eachR¹⁹ is independently selected from the group consisting of hydrogen,hydroxyl, halo, optionally substituted C₁-C₄ alkyl, C(O)R¹⁰, C(O)OR¹⁰,NO₂, S(O)_(j)R¹⁰ and S(O)_(j)NR¹⁰R¹¹; or a pharmaceutically acceptablesalt thereof.
 6. The compound of claim 4, wherein R¹⁶ is cyano; or apharmaceutically acceptable salt thereof.
 7. The compound of claim 1,wherein the compound has the Formula (Ib):

or a pharmaceutically acceptable salt thereof; wherein each R²¹ isindependently selected from the group consisting of hydrogen, optionallysubstituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂ alkenyl,optionally substituted C₂-C₁₂ alkynyl, optionally substituted C₃-C₁₅cycloalkyl, optionally substituted C₃-C₁₅ cycloalkenyl, halo, cyano,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heterocyclyl, OR¹⁰, NO₂, S(O)_(j)R¹⁰,S(O)_(j)NR¹⁰R¹¹; C(O)R¹⁰, C(O)OR¹⁰, C(O)—R¹³—N(R¹⁰)R¹¹,N(R¹⁰)C(O)N(R¹⁰)R¹¹, NR¹⁰R¹¹, and N(R¹⁰)C(O)R¹⁰; wherein z is an integerfrom 1 to
 5. 8. The compound of claim 7, wherein z is 1 or 2, and eachR²¹ is independently selected from the group consisting of hydrogen,hydroxyl, halo, optionally substituted C₁-C₄ alkyl, C(O)R¹⁰, C(O)OR¹⁰,NO₂, S(O)_(j)R¹⁰ and S(O)_(j)NR¹⁰R¹¹; or a pharmaceutically acceptablesalt thereof.
 9. The compound of claim 8, wherein each R²¹ isindependently selected from the group consisting of hydrogen, hydroxyland halo, or a pharmaceutically acceptable salt thereof.
 10. Thecompound of claim 3, wherein R¹⁷ is optionally substituted heteroaryl;or a pharmaceutically acceptable salt thereof.
 11. The compound of claim10, wherein R¹⁷ is an optionally substituted heteroaryl containing oneor more ring nitrogen atoms; or a pharmaceutically acceptable saltthereof.
 12. The compound of claim 11, wherein R¹⁷ is optionallysubstituted pyridyl; or a pharmaceutically acceptable salt thereof. 13.The compound of claim 7, wherein R¹⁶ is cyano; or a pharmaceuticallyacceptable salt thereof.
 14. The compound of claim 1, wherein R^(1a) isselected from the group consisting of hydrogen, C(O)OR¹⁰, C(O)R¹⁰,optionally substituted C₁-C₁₂ alkyl, optionally substituted C₂-C₁₂alkenyl, optionally substituted C₂-C₁₂ alkynyl, optionally substitutedC₃-C₁₅ cycloalkyl, optionally substituted C₃-C₁₅ cycloalkenyl, halo,cyano, optionally substituted aryl, optionally substituted heteroaryl,and optionally substituted heterocyclyl; or a pharmaceuticallyacceptable salt thereof.
 15. The compound of claim 14, wherein R^(1a) isselected from the group consisting of hydrogen, C(O)OR¹⁰, C(O)R¹⁰,optionally substituted alkyl, halo, optionally substituted phenyl,optionally substituted furanyl, optionally substituted thienyl,optionally substituted thiazolyl, and optionally substituted oxazolyl;and wherein R^(1b), R^(1c), R^(1d) and R^(1e) are each hydrogen, or apharmaceutically acceptable salt thereof.
 16. The compound of claim 1,wherein R⁴ is a direct bond, an optionally substituted methylene or anoptionally substituted ethylene, or a pharmaceutically acceptable saltthereof.
 17. The compound of claim 16, wherein R⁴ is methylene, or apharmaceutically acceptable salt thereof.
 18. The compound of claim 1,wherein R⁷ is hydrogen or optionally substituted C₁-C₆ alkyl, or apharmaceutically acceptable salt thereof.
 19. The compound of claim 18,wherein R⁷ is hydrogen, C₁-C₆ alkyl optionally substituted with OR¹⁰, orC₁-C₆ alkyl optionally substituted with NR¹⁰R¹¹, or a pharmaceuticallyacceptable salt thereof.
 20. The compound of claim 19, wherein R⁷ ishydrogen or methyl, or a pharmaceutically acceptable salt thereof. 21.The compound of claim 1 selected from the following compounds, or apharmaceutically acceptable salt thereof:

X Y PhO NH₂ PhO

PhO

PhO

PhO

PhO

PhO

OPh

—OPh

—OPh

—OPh

—OPh

—OPh


22. A pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and a compound of claim 1, or a pharmaceuticallyacceptable salt thereof.
 23. The compound of claim 4, wherein r is 0 andR⁴ is a direct bond; or a pharmaceutically acceptable salt thereof. 24.The compound of claim 7, wherein r is 0 and R⁴ is a direct bond; or apharmaceutically acceptable salt thereof.
 25. The compound of claim 10,wherein r is 0 and R⁴ is a direct bond; or a pharmaceutically acceptablesalt thereof.
 26. The compound of claim 18, wherein r is 0 and R⁴ is adirect bond; or a pharmaceutically acceptable salt thereof.